Introduction
Angiosarcoma (AS) is a rare and aggressive malignancy originating from the endothelial cells of blood or lymphatic vessels [1]. Representing a small fraction, about 1-2%, of all soft tissue sarcomas in humans, it predominantly affects adults and the elderly [1-3]. This heterogeneous group of sarcomas can manifest throughout the body [4], with a predilection for cutaneous sites (approximately 60% of cases), particularly the head and neck region. Angiosarcomas can also arise in soft tissues, visceral organs, bone, and the retroperitoneum [1, 4].
Characterized by its infiltrative nature, angiosarcoma exhibits a high propensity for local recurrence and distant metastasis [1, 5, 6]. At initial presentation, 16% to 44% of cases already present with advanced or metastatic disease, contributing to a poor overall survival (OS) ranging from just 6 to 16 months [7].
While the precise pathogenesis of angiosarcoma remains elusive, several risk factors have been identified, including chronic lymphedema, prior radiation exposure, environmental carcinogens (such as vinyl chloride, thorium dioxide, and arsenic), and certain genetic syndromes [1, 2, 8]. Epidemiological studies indicate a roughly equal gender distribution, with occurrence possible at any age. However, cutaneous angiosarcoma shows a notable predilection for older males, typically between 60 and 71 years of age [9].
Angiosarcoma Diagnosis is often challenging due to the non-specific nature of its symptoms, making differentiation from other malignancies like anaplastic melanoma and epithelial carcinomas difficult [2, 10, 11]. While imaging modalities like ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) play a role, they have limitations in definitive diagnosis [11]. Consequently, histological examination and immunohistochemical confirmation are crucial for accurate angiosarcoma diagnosis [6, 12]. Histologically, angiosarcoma is characterized by a spectrum of cell morphologies, including spindled, polygonal, epithelioid, and primitive round cells, all expressing vascular and endothelial antigens such as Factor-VIII, CD31, CD34, and VEGF upon immunohistochemical analysis [1, 2, 10, 11].
Delayed angiosarcoma diagnosis and the rarity of these tumors contribute to complexities in determining optimal treatment strategies and prognostic factors. Radical surgery followed by adjuvant radiotherapy is considered the current standard of care [2, 6, 10]. Despite concerns regarding side effects, conventional cytotoxic chemotherapy remains a frequent approach for inoperable and metastatic tumors [2, 4]. Furthermore, targeted therapies and immunotherapy are emerging as promising avenues in angiosarcoma treatment [4, 13, 14].
Etiology of Angiosarcoma
In a majority of angiosarcoma cases, the underlying cause remains unknown. However, several established etiological factors significantly contribute to the development of this disease. These include radiation exposure, chronic lymphedema, environmental carcinogens, and genetic syndromes.
Radiation-Induced Angiosarcoma
Radiation is a well-recognized risk factor for both benign and malignant tumors. Retrospective studies have linked radiation exposure to an increased risk of tumor development through radiation-induced gene mutations and associated chronic lymphedema [15, 16]. Epidemiological surveys identify diagnostic and therapeutic radiation in medical settings and occupational exposure as common sources [17].
Radiation-induced sarcomas, particularly breast sarcomas, are a notable subtype of secondary sarcomas due to the widespread use of radiotherapy in early-stage sarcoma treatment, especially breast cancer [18, 19]. Radiation-induced breast sarcomas often exhibit a long latency period, with a median disease-free interval of 5-10 years post-radiation [18, 20, 21]. This necessitates long-term follow-up beyond the standard 5-year oncological surveillance to ensure prompt detection of recurrence [20].
The precise relationship between radiotherapy and angiosarcoma is still under investigation. However, studies suggest that with increased radiotherapy utilization in angiosarcoma treatment and improved survival rates for cancer patients overall, the risk of radiation-induced angiosarcoma is rising [22, 23]. A correlation between higher radiotherapy doses and angiosarcoma incidence may also exist [24].
Nevertheless, it’s crucial to emphasize that the overall risk of radiation-induced angiosarcoma remains small and negligible compared to the substantial benefits of radiotherapy in cancer treatment.
Chronic Lymphedema and Angiosarcoma (Stewart-Treves Syndrome)
Chronic lymphedema stands as another recognized risk factor for angiosarcoma. The association between long-standing chronic lymphedema and angiosarcoma is well-established and termed Stewart-Treves syndrome (STS) [25]. STS is commonly observed in women following breast-conserving surgery combined with adjuvant radiotherapy. Adjuvant radiotherapy for early breast cancer is considered a contributing factor to STS development [17, 25-27]. Other potential causes of chronic lymphedema that can lead to STS include parasitic infections like filariasis, Milroy’s disease, idiopathic, congenital, traumatic, and filarial lymphedema [28].
STS accounts for approximately 5% of all angiosarcomas, typically manifesting 5-15 years after local treatment involving surgery and radiotherapy [27]. The prognosis for STS is unfortunately poor, with a survival rate of approximately 10 months [26]. The exact mechanism linking chronic lymphedema and secondary angiosarcoma remains debated. Genetic mutations in tumor suppressor genes, such as p53 and MYC, are considered potential cofactors in some cases [26, 29].
Environmental Carcinogens and Hepatic Angiosarcoma
While the etiology of hepatic angiosarcomas is often undetermined in about 75% of cases [30], environmental carcinogens are the most recognized risk factors for this specific subtype. These include exposure to vinyl chloride monomer and other industrial materials, iatrogenic exposure to colloidal thorium dioxide (Thorotrast) used in radiological examinations in the past, chronic arsenic ingestion, and androgenic steroids [31, 32]. Occupational exposure is implicated in the majority of hepatic angiosarcoma cases [33].
Genetic Syndromes and Predisposition to Angiosarcoma
Approximately 3% of primary angiosarcomas are associated with gene-induced or gene-associated diseases. These include bilateral retinoblastoma, Neurofibromatosis type 1 (Recklinghausen neurofibromatosis), Ollier disease, Maffucci syndrome, xeroderma pigmentosa, and Klippel-Trenaunay syndrome, among others. Familial syndromes are also linked to an increased risk of angiosarcoma [34]. Recent genomic analyses have revealed the dysregulation of angiogenic pathways as a significant factor in angiosarcoma etiology. Furthermore, associations between tumor suppressor genes and angiosarcomas have been identified, although the clinical significance of these findings is still under investigation [6, 8].
Epidemiology of Angiosarcoma
Angiosarcoma, a highly malignant endothelial tumor, constitutes about 2-3% of all adult soft tissue sarcomas. It can arise in any bodily location but demonstrates a notable predilection for the skin and superficial soft tissues [8, 10]. Cutaneous angiosarcoma accounts for approximately two-thirds of all cases [10]. Due to its aggressive nature and tendency for distant metastasis, the lungs and brain are common sites of spread, resulting in a poor prognosis [1]. Historical studies report a 5-year survival rate for angiosarcoma patients ranging from 30-40%, with an overall survival of 6 to 16 months. Local recurrence or metastasis occurs in a significant proportion, 20-40% of patients [1, 10, 35]. Epidemiological data indicates a higher incidence of angiosarcoma in older males, particularly those aged 60-70 years, especially in cases of cutaneous angiosarcoma [36, 37].
Angiosarcoma Diagnosis: Clinical and Pathological Approaches
Angiosarcoma diagnosis presents a considerable challenge due to the non-specific nature of its clinical presentations. Accurate and timely angiosarcoma diagnosis is critical for appropriate management and improving patient outcomes. The diagnostic process encompasses clinical evaluation, advanced imaging techniques, and definitive pathological examination.
Clinical Presentation of Angiosarcoma
The diverse locations of angiosarcoma result in a wide range of clinical presentations. Common symptoms are often non-specific and can include abdominal discomfort, nausea, vomiting, and altered bowel habits [6, 38]. Cutaneous angiosarcoma may manifest as single or multiple bluish or reddish nodules that are prone to ulceration and bleeding [8]. Hepatic angiosarcoma typically presents with right upper quadrant abdominal pain, jaundice, and fatigue [31]. Lung and other visceral angiosarcomas, common sites for metastases, may present with pleural disease, pleural effusion, or dyspnea [21, 24]. These varied and often subtle initial signs underscore the difficulty in early angiosarcoma diagnosis based solely on clinical presentation.
Diagnostic Imaging in Angiosarcoma
Given the rarity and non-specific clinical presentations, differentiating angiosarcoma from other malignant tumors is challenging [11]. Diagnostic imaging plays a crucial role in the initial evaluation and suspicion of angiosarcoma diagnosis. Ultrasound, CT, and MRI are commonly employed imaging modalities.
Ultrasonography is frequently used to detect effusions and lesions in visceral organs. Contrast-enhanced ultrasound has been reported as a valuable tool in the diagnosis of hepatic angiosarcoma by Rauch et al. [39]. In cardiac angiosarcoma evaluation, transthoracic echocardiography demonstrates high sensitivity in tumor detection and is useful for assessing tumor location, size, and shape [40]. However, ultrasonography has limitations, particularly with larger masses, which may be ill-defined or poorly visualized [41].
Compared to ultrasonography, CT and MRI provide more detailed information about tumors [11]. CT findings in lung angiosarcoma can include pulmonary nodules, infiltrations, and ground-glass opacity (GGO) [42]. Cardiac angiosarcomas on CT often appear as heterogeneous enhancing masses [42]. However, due to the histological characteristics of angiosarcoma, CT may have limitations in distinguishing suspected tumor masses from other conditions. MRI excels over CT in differentiating between thrombus and tumor mass by providing detailed tissue characterization [11, 43, 44]. While both CT and MRI are sensitive in detecting angiosarcomas, immunohistochemical and pathological confirmation remain essential for a definitive angiosarcoma diagnosis.
Pathological Examination: The Gold Standard for Angiosarcoma Diagnosis
Due to the non-specificity of most diagnostic imaging features, histological and immunohistochemical examinations are indispensable for a definitive angiosarcoma diagnosis.
In clinical practice, histological specimens are typically obtained through three main approaches:
- Tumor Resection and Biopsy: Initial tumor resection or biopsy followed by a second surgery after pathological angiosarcoma diagnosis.
- Rapid Pathological Examination (Frozen Section): Performed during tumor resection, with expanded resection carried out immediately following angiosarcoma diagnosis.
- Hollow Needle Puncture Biopsy: Performed preoperatively, with surgical resection proceeding after pathological angiosarcoma diagnosis.
Histologically, angiosarcoma exhibits a wide spectrum of appearances, ranging from well-differentiated to poorly differentiated variants. Well-differentiated angiosarcoma is characterized by numerous irregular vascular channels lined by endothelial cells. In contrast, poorly differentiated angiosarcoma tissues may display spindle-shaped, polygonal, epithelioid, and primitive round cells with increased mitotic activity and poorly formed vascular spaces. The heterogeneous cytoarchitectural features in poorly differentiated tumors can make histological identification of angiosarcoma challenging [8, 45-47].
Immunohistochemical examination plays a critical role in the diagnosis of less-differentiated angiosarcomas. Angiosarcomas characteristically express endothelial markers, including Factor-VIII-related antigen (Factor-VIIIRA), CD31, CD34, and vascular endothelial growth factor (VEGF). Among these, CD31 is the most consistently expressed marker, found in over half of angiosarcoma cases. CD31 is considered the gold standard for angiosarcoma diagnosis due to its high sensitivity and specificity. Notably, cytokeratin expression has been observed in epithelioid angiosarcomas, potentially leading to misdiagnosis as poorly differentiated carcinomas [1, 6, 42, 46, 48]. Therefore, a comprehensive immunohistochemical panel is crucial for accurate angiosarcoma diagnosis, especially in challenging cases.
Gene Alterations in Angiosarcoma
Cytogenetically, angiosarcoma is marked by the upregulation of vascular-specific receptor tyrosine kinases, such as TIE1, KDR, TEK, and FLT1 [8, 49]. While the genetic mutations in most primary angiosarcomas remain undefined, angiogenesis-related genes have been confirmed to play key roles in secondary angiosarcomas. These include MYC gene amplification and mutations in protein tyrosine phosphatase receptor type B (PTPRB) and phospholipase C gamma 1 [1, 50].
The proto-oncogene MYC, located on chromosome 8q24, shows amplification as a prominent feature in secondary angiosarcomas [51, 52]. Studies have linked MYC gene amplification to ultraviolet and sunlight exposure and found it in over 80% of radiation-induced angiosarcoma cases [51, 53]. Historically, MYC amplification was considered specific to secondary angiosarcomas, with no evidence in primary cases. However, recent findings in a small series of primary cutaneous angiosarcoma cases revealed MYC overexpression in 9 of 38 (24%) cases [54], suggesting a broader role for MYC in angiosarcoma development.
The FLT4 gene, located on chromosome 5q35, encodes for VEGFR3 (Vascular endothelial growth factor receptor 3), which is thought to be involved in lymphatic differentiation [55]. FLT4 gene amplification occurs in approximately 25% of secondary angiosarcomas, often alongside MYC amplification, leading to high FLT4 mRNA expression [56]. This finding suggests targeting FLT4 as a potential therapeutic strategy for secondary angiosarcomas.
Rearrangements of the CIC gene, a transcriptional repressor on chromosome 19q13.1, have been reported in 9% (9/98) of patients with primary cutaneous angiosarcoma [53]. Additionally, mutations in PTPRB and PLCG1, two angiogenesis-signaling genes, have emerged as potential therapeutic targets in secondary angiosarcoma [57]. Further research into these genetic alterations is crucial for advancing angiosarcoma diagnosis and targeted therapies.
Treatment Strategies for Angiosarcoma
Due to the rarity of angiosarcomas and the lack of prospective clinical trial data, the optimal management strategy remains debated. Current treatment options include surgery, radiotherapy, and chemotherapy. Treatment outcomes are highly variable and depend on factors such as tumor site, size, resectability, and tumor type. Targeted therapies and immunotherapy are also under investigation as promising treatment modalities.
Surgical Management of Angiosarcoma
Radical surgery remains the cornerstone of angiosarcoma treatment. However, the extensive nature and rapid progression of the disease often result in positive surgical margins after resection [1, 45]. Generally, only very early-stage angiosarcoma treated with radical surgery achieving negative margins offers the best prognosis [58, 59]. The impact of surgical margin status on angiosarcoma outcome remains somewhat unclear. Some studies suggest positive margins correlate with decreased overall survival and increased metastasis risk, while others have not demonstrated this correlation [1, 14, 60]. Despite these inconsistencies, achieving negative surgical margins is generally associated with improved patient survival and better outcomes.
Angiosarcomas of the head and neck often present challenges for surgical resection due to their proximity to critical anatomical structures and metastatic potential. Even with extensive surgery, achieving negative surgical margins is difficult, and local recurrence and distant metastasis rates can be as high as 30-100% in these cases [1, 58, 60, 61].
Adjuvant radiotherapy following surgery is frequently used in patients with negative microscopic margins or unresectable disease to mitigate the risk of local recurrence. Radical surgery combined with adjuvant radiotherapy has demonstrated improved outcomes and survival rates.
Radiotherapy for Angiosarcoma
While surgery is considered the most reliable curative treatment for angiosarcoma, it may be contraindicated in some patients, particularly older individuals, and recurrence rates remain high even with surgery [1, 10]. Over the past three decades, advancements in radiotherapy technologies have shown a trend toward improved outcomes in angiosarcoma treatment [45].
Despite limited prospective data, current evidence supports radiotherapy’s effectiveness in inoperable angiosarcoma cases and in reducing postoperative recurrence risk [22, 24, 62].
Definitive radiotherapy is increasingly used for unresectable tumors, such as angiosarcomas of the head and neck. However, the optimal radiotherapy management for angiosarcomas remains unclear due to limited prior research [1, 62]. Studies suggest that higher radiation doses (>70 Gy) may improve local control and overall survival when radiotherapy is used as a standalone treatment [1, 62, 63].
Currently, no formal observational trials have definitively established whether radiotherapy alone is adequate for angiosarcomas. However, adjuvant radiotherapy following radical surgery is recognized as an optimal combination for this disease [1, 62]. Retrospective studies have shown better 5-year overall survival rates in combined therapy groups compared to surgery alone. Despite data limitations, these outcomes indicate that adjuvant radiotherapy following radical surgery holds promise for improving overall survival in angiosarcoma patients.
Factors influencing radiotherapy efficacy include treatment volume, dose, radiation modality, and technique. Large retrospective studies often recommend large doses (>50 Gy) with wide fields for controlling extensive angiosarcomas, while postoperative low-dose radiotherapy is effective for local disease following resection within 3 weeks [62, 64]. Given the risk of radiation-induced angiosarcoma, further radiotherapy must be used cautiously in tumor treatment.
Chemotherapy for Angiosarcoma
Due to the aggressive nature of angiosarcomas, approximately 50% of patients with localized disease will develop local recurrence and distant metastases [1]. While controversies persist regarding systemic chemotherapy for metastatic angiosarcoma and the optimal choice of agents, adjuvant chemotherapy is generally believed to offer limited benefits after surgery or radiotherapy. Cytotoxic chemotherapy remains the primary treatment approach for metastatic angiosarcoma [2].
Primary chemotherapy agents used in angiosarcoma include taxanes, doxorubicin, liposomal doxorubicin, and ifosfamide. However, the use of chemotherapy in many angiosarcoma patients, who are often elderly, is limited by comorbidities and the risk of agent-related toxicities [1, 2, 14].
Anthracyclines in Angiosarcoma Chemotherapy
Doxorubicin, an anthracycline, serves as the backbone of chemotherapy regimens for soft tissue sarcomas, providing a median overall survival of 8-14 months and reducing metastasis rates [65]. A pooled analysis of angiosarcoma patients from 11 prospective EORTC clinical trials of first-line anthracycline-based regimens showed that angiosarcomas respond similarly to first-line anthracycline-based regimens compared to other soft tissue sarcomas, challenging the notion of inherently poor prognosis [66].
Combining doxorubicin with ifosfamide has demonstrated improved survival in sarcomas compared to single-agent anthracycline [2]. Olaratumab, a recombinant human immunoglobulin G subclass 1 (IgG1) monoclonal antibody, has also shown promise in improving both progression-free and overall survival when combined with doxorubicin for first-line angiosarcoma treatment [67]. However, due to overlapping toxicities, these combinations often require lower doses to minimize complications, and their full potential warrants further investigation [65, 67].
Liposomal doxorubicin, compared to traditional doxorubicin in a randomized study, showed similar outcomes in soft tissue sarcoma treatment with a more favorable toxicity profile, characterized by less myelotoxicity but increased skin toxicity [66]. Several smaller studies have corroborated these findings [68]. Overall, liposomal doxorubicin is considered an optimal option for angiosarcoma patients who cannot tolerate the toxicity of doxorubicin.
Taxanes in Angiosarcoma Chemotherapy
Paclitaxel is clinically recognized as an active monotherapy for angiosarcomas and is frequently used as first- or second-line treatment for metastatic disease. Larger retrospective studies have supported the efficacy of taxanes [2]. Fata et al. initially reported that 90% of scalp angiosarcoma patients achieved a positive response with weekly paclitaxel, with a median progression-free survival of 5 months [69]. Furthermore, a clinical trial by Apice et al. in patients younger than 75 with advanced or metastatic angiosarcoma indicated that weekly paclitaxel is an effective and well-tolerated treatment, with a median overall survival of 18.6 months [70]. However, phase II trials investigating combinations of weekly paclitaxel with other targeted agents for advanced angiosarcoma have yielded disappointing response rates [71, 72].
Despite ongoing debate regarding the optimal selection and sequencing of anthracycline- and taxane-based chemotherapy, both anthracycline and taxane chemotherapy remain active and frequently recommended treatment options for angiosarcomas.
Targeted Therapy for Angiosarcoma
Vascular Endothelial Growth Factor (VEGF) Targeted Therapy
Angiogenesis, the formation of new capillary blood vessels, is crucial for normal human growth and development [73, 74]. Proangiogenic growth factors and their receptors, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), play significant roles in cancer development and progression [1, 2, 14, 75]. Understanding these molecular pathogeneses is vital for identifying new therapeutic targets for angiosarcomas.
VEGF is a key angiogenic factor, with overexpression observed in various sarcoma subtypes, including angiosarcoma [76, 77]. Animal model studies have demonstrated that high VEGF expression can lead to rapidly growing malignant tumors [78]. The therapeutic potential of targeting VEGF and its receptor (VEGFR) in angiosarcoma has been demonstrated in vitro [79].
Tyrosine kinase inhibitors (TKIs), particularly sorafenib and pazopanib, have been used in targeted therapy for angiosarcomas by inhibiting the VEGF/VEGFR signaling pathway [80]. A phase II clinical trial by Penel et al. confirmed the utility of sorafenib, a small molecule B-RAF and VEGFR inhibitor, in angiosarcoma treatment [81]. Pazopanib, another multi-targeted TKI inhibiting VEGFR and PDGFR with significant suppressive activity, has also shown benefit in angiosarcoma treatment [82, 83].
Although some angiosarcoma cases have shown disappointing responses to VEGF-targeted agents, VEGF pathway blockade remains a promising therapeutic avenue for cancer patients and requires further research [84].
Adrenergic Receptor Targeted Therapy
Retrospective studies in large patient cohorts have shown high expression levels of beta adrenergic receptors in malignant vascular tumors, including angiosarcomas [85]. Amaya et al. reported that non-selective beta blockers, such as propranolol, improved outcomes in metastatic angiosarcoma patients, extending median progression-free survival to 9 months and median overall survival to 36 months [86]. Furthermore, case series investigating the combination of bi-daily propranolol (40 mg) and weekly metronomic vinblastine (6 mg/m2) in angiosarcoma patients reported a 100% response rate and a median progression-free survival of 11 months [87, 88].
Immunotherapy for Angiosarcoma
Programmed death 1 (PD-1) and its receptors, including ligand-1 (PD-L1) and ligand-2 (PD-L2), have emerged as effective therapeutic targets for various malignancies [89, 90]. Studies have demonstrated encouraging survival outcomes in melanoma treatment using anti-PD-1 antibodies [91, 92]. While large-scale clinical trials are lacking, smaller trials have shown the curative potential of anti-PD-1 antibodies in angiosarcoma [93]. Although definitive evidence for similar outcomes in angiosarcoma compared to melanoma with anti-PD-1 antibody treatment is still needed, the potential of immunotherapy in angiosarcoma is promising.
Conclusion
Angiosarcoma is a highly malignant endothelial tumor characterized by high rates of local and distant recurrence. Its pathological diversity necessitates histological examination as the definitive method for angiosarcoma diagnosis. The etiology of most angiosarcoma cases remains unclear. Current treatments face limitations, but surgical resection combined with adjuvant radiotherapy remains the mainstay for localized angiosarcomas. Preventing recurrence and metastasis after treatment remains a significant challenge. Chemotherapy is the primary treatment option for metastatic angiosarcoma, despite toxicities associated with commonly used agents. Advancements in understanding disease biology are making biological therapies a promising area for developing optimal treatment strategies for this rare disease. Targeted therapies hold hope for improving progression-free and overall survival and potentially achieving complete cures for angiosarcoma. Further prospective studies are essential for improving prevention, early angiosarcoma diagnosis, and effective therapy for this challenging malignancy.
Acknowledgements
We kindly thank MeiYu Fang for providing useful comments, participating in revision of the manuscript, and reediting the resubmitted manuscript for grammar and wording. We also kindly thank the editor and reviewers for their careful review and valuable comments, which have significantly improved the manuscript. This study was supported by a National Natural Science Foundations of China (Grant Number: 81702653), and a grant from the Zhejiang Medical and Health Science and Technology Plan (Grant Number: 2018253753). The funding body had no role in the design, data collection, analysis, interpretation or manuscript writing of this study.
Disclosure of conflict of interest
None.
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